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Metastases

Authors: Tamadar Al Doheyan, M.D., Shilpa Jain, M.D.

Editorial Board Member: Kimberley J. Evason, M.D., Ph.D.

Deputy Editor-in-Chief: Aaron R. Huber, D.O.

Last author update: 11 September 2024

Last staff update: 11 September 2024

Copyright: 2002-2024, PathologyOutlines.com, Inc.

PubMed Search: Metastases to liver

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Table of Contents

Cite this page: Al Doheyan T, Jain S. Metastases. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/livertumormet.html. Accessed December 3rd, 2024.

Definition / general

Metastatic neoplasms are the most common malignant liver tumors, with hepatocellular carcinoma (HCC) being the most common primary liver tumor
Carcinomas originating in the colon, lung, breast and pancreas are the most common liver metastases, although sarcomas, lymphomas and melanomas can also spread to the liver

Essential features

Metastatic tumors can morphologically mimic primary liver tumors (HCC and cholangiocarcinoma [CCA]), posing challenges in diagnosis
- Also, primary liver sarcomas (e.g., epithelioid hemangioendothelioma and angiosarcoma) are morphologically indistinguishable from their metastasizing counterparts
Metastatic tumors from different sites may share similar morphological and even immunohistochemical features (e.g., adenocarcinoma from GI, pancreaticobiliary, lung)
Albumin ISH can help to distinguish between primary HCC and intrahepatic cholangiocarcinoma from metastatic carcinoma, though exceptions exist; for example, metastatic hepatoid adenocarcinoma to liver can be positive for albumin ISH (usually arising from stomach, lung or pancreas)

ICD coding

ICD-10: C78.7 - secondary malignant neoplasm of liver and intrahepatic bile ducts

Epidemiology

Liver is one of the most common sites for cancer metastasis (25% of all cases) (J Clin Oncol 1995;13:2094)
HCC predominantly arises in cirrhotic livers, although ~20% can develop in noncirrhotic livers (World J Hepatol 2019;11:1)
Metastatic tumors more frequently manifest in noncirrhotic livers, with a low prevalence in cirrhotic livers (World J Hepatol 2019;11:1)

Pathophysiology

Portal veins receive venous drainage from the pancreas, spleen and most of the gastrointestinal tract, leading to liver metastasis from a wide variety of abdominal and extra-abdominal malignancies
Large vessel invasion in most carcinomas (e.g., colorectal carcinomas with extramural large vessel [venous] invasion) have high probability of metastasis to the liver

Diagrams / tables

Contributed by Tamadar Al Doheyan, M.D. and Shilpa Jain, M.D.

Morphologic pattern approach

Epithelioid pattern approach

Clinical features

Patients may present with a variety of symptoms depending on disease burden and location; these include abdominal pain, ascites, jaundice, weight loss and fatigue

Diagnosis

Reviewing clinical (including tumor markers) and radiological findings
Morphologic pattern approach is helpful in directing the ancillary testing (see Diagrams / tables)
Preserving tissue for future testing, since molecular alteration is helpful for diagnosis and important for prognosis and targeted therapy
Comparison between the morphologic and immunohistochemical findings of the hepatic lesion with any prior tumor biopsies or resections is crucial for accurate diagnosis and treatment planning

Laboratory

Serum tumor markers, including AFP, CEA, CA 19-9, CA125, can be elevated depending on tumor location

Radiology description

Metastatic tumors typically present as multiple lesions and develop in noncirrhotic livers, often accompanied by metastasis elsewhere (World J Hepatol 2019;11:1)
HCC tends to be singular or multiple and commonly arises within the parenchyma of a cirrhotic liver (World J Hepatol 2019;11:1)
Radiologists use imaging diagnostic algorithms, specifically Liver Imaging Reporting and Data System (LI-RADS), for HCC diagnosis
- LI‐RADS categories suggestive of malignancy include LR 4 (probably HCC), LR 5 (definitely HCC), LR M (probably or definitely malignant, not specific for HCC) and LR TIV (malignancy with tumor in vein) (Clin Liver Dis (Hoboken) 2021;17:409)

Prognostic factors

Metastatic tumors indicate a worse prognosis; however, metastasis may be present as a single nodule, in which case it may be resected surgically and may have a better prognosis
Colon cancer can exhibit any pattern and can predict response to therapy, whereas nonintestinal carcinomas like breast cancer and uveal melanoma often show the replacement pattern, associated with a poorer prognosis (J Oncol 2019;2019:6280347)

Case reports

28 year old African American woman with metastatic breast carcinoma presented with liver failure due to diffuse infiltration of the hepatic sinusoids (Radiol Case Rep 2021;16:1005)
42 year old woman with glioblastoma multiforme and liver metastasis (No To Shinkei 1995;47:772)
53 year old man with gastric carcinoma and synchronous oligometastatic lesion in liver VIII segment underwent a total gastrectomy combined with metastasectomy (Curr Probl Cancer 2017;41:222)
59 year old man with solitary fibrous tumor involving the liver (World J Surg Oncol 2011;9:37)
68 year old man with colorectal liver metastasis that occurred 10 years after laparoscopic colectomy (Surg Case Rep 2022;8:144)
71 year old man with late hepatic metastasis from a duodenal gastrointestinal stromal tumor (Int J Surg Pathol 2015;23:317)

Treatment

Metastatic tumors are usually treated with systemic therapy and surgical management is usually avoided; thus, it is crucial to distinguish if the tumor is primary or metastatic when possible
Surgical metastatectomy / partial hepatectomy is only preferred for metastatic colorectal carcinoma, as it improves prognosis

Gross description

Pathologists seldom encounter liver resections from metastatic tumors except in cases that originate from the colon
Metastatic tumors typically present as multiple lesions and HCC tends to be singular
In partial hepatectomy for colorectal cancer status postneoadjuvant therapy, it is essential to document key features including the number of tumors, size, percentage of necrosis (both grossly and microscopically) and distance from the resection margin

Gross images

Images hosted on other servers:

Multiple metastases

Colonic adenocarcinoma metastases

Frozen section description

Liver lesions seen intraoperatively in patients with a known primary are usually sampled to rule out metastasis and determine patient's surgical and intraoperative management; if this lesion is metastasis, the surgery will likely be aborted and the patient will be treated systemically
Other common liver lesions sent for frozen section are bile duct adenoma and bile duct hamartoma that can mimic adenocarcinoma
- Being aware of this diagnosis is crucial for patient's intraoperative management

Microscopic (histologic) description

Glandular / pseudoglandular pattern
- Glandular pattern mimicking CCA and pseudoglandular HCC (see Diagrams / tables for more differential and immunohistochemistry panel)
- Pancreaticobiliary metastases to liver usually show angulated glands with desmoplasia
- Colon carcinoma metastatic to liver: tubular, papillary or cribriform patterns of columnar cells with basophilic cytoplasm and elongated nuclei, extensive necrosis
- Neuroendocrine tumors have different growth patterns, including trabecular, cords, nests and tubuloglandular; usually eosinophilic rich cytoplasm pattern (see Diagrams / tables for other differentials and immunohistochemistry panel) (Br J Cancer 2022;127:988)
Sinusoidal growth patten
- Sinusoidal growth patten, the main 2 differentials include lobular breast carcinoma and lymphoma (Br J Cancer 2022;127:988)
- Acinar cell carcinoma can have different architectures and growth patterns, including cystic, acinar, glandular (see Diagrams / tables for other differentials and immunohistochemistry panel) (Br J Cancer 2022;127:988)
Spindle cell pattern
- Gastrointestinal stromal tumor (GIST) metastatic to liver may include spindle or epithelioid cells or mixed (Br J Cancer 2022;127:988)
- Metastatic melanoma to liver may replace hepatic cords and grow in a trabecular pattern with endothelial lining (Br J Cancer 2022;127:988)
- Angiosarcoma can be primary or metastatic
  - Morphologically, can be mass forming (vasoformative, solid / epithelioid and spindle cell) or non-mass forming (sinusoidal infiltration and peliotic-like) (Br J Cancer 2022;127:988)

Microscopic (histologic) images

Contributed by Shilpa Jain, M.D., Raul S. Gonzalez, M.D. and Semir Vranić, M.D., Ph.D.

Intrahepatic
cholangiocarcinoma

Pancreatic ductal adenocarcinoma

Adenocarcinoma of pancreatic primary

Ductal adenocarcinoma of breast primary

Metastatic renal cell carcinoma

Metastatic squamous cell carcinoma

Diffuse large B cell lymphoma

CLL / SLL involving the liver

Metastatic angiosarcoma

Metastatic leiomyosarcoma

Ocular melanoma metastatic to liver

Melanoma metastatic to liver

Intrahepatic
cholangiocarcinoma,
BAP1

Ductal adenocarcinoma of breast primary, GATA3

Metastatic renal cell carcinoma, PAX8

Metastatic angiosarcoma, CD31

Melanoma metastatic to liver, S100

Melanoma metastatic to liver, MelanA

Melanoma metastatic to liver, HMB45

Positive stains

See Diagrams / tables

Molecular / cytogenetics description

Preserving tissue for future testing of molecular alteration is helpful
- For determining the site of the primary tumor in a patient with unknown primary for diagnosis
- For prognosis and targeted therapy

Sample pathology report

Liver, CT guided fine needle biopsy:
- Moderately differentiated adenocarcinoma, CK7 positive (see comment)
- Comment: Histological sections show a moderately differentiated adenocarcinoma. Immunohistochemical stains show that these tumor cells are only positive for CK and negative for HepPar1, arginase1, CK20, CDX2, synaptophysin, chromogranin, TTF1, PSA, p40, GATA3, SALL4, PLAP and OCT4. Ki67 proliferative index is high.
- The histomorphology and extensive immunohistochemistry is not site specific and the differential includes pancreaticobiliary (including intrahepatic and extrahepatic), upper gastrointestinal primary, lung, among others. Please correlate with patient's clinical history and imaging studies to locate the primary site of this tumor.
- If albumin ISH was performed, an additional comment can be added
  - Tumor cells are positive for albumin ISH. This is supportive of an intrahepatic malignancy in the appropriate clinical setting. Of note, as per literature, albumin ISH has high sensitivity for primary liver carcinoma, although this can also be positive in other adenocarcinomas not of biliary origin. Please correlate with patient's clinical history and imaging studies.
Liver mass, segment 2, laparoscopic partial left lobe liver resection:
- Metastatic adenocarcinoma, morphologically consistent with colorectal primary (see comment)
- Single focus
- Tumor size: 2.5 cm
- Tumor viability ~40%
- Resection margins negative for tumor, with a clearance of ~1 mm
- Comment: Background liver with mild nonspecific portal inflammation, no significant steatosis or fibrosis noted.
- Selected slides from previous colon biopsy have been reviewed and show similar histomorphologic features; thus, the findings in this case are best in keeping with a metastatic adenocarcinoma from patient's known history of colorectal primary.

Differential diagnosis

Hepatocellular carcinoma:
- Positive for hepatocyte markers (glypican 3, HepPar1, arginase1), pCEA and CD10 show canalicular staining pattern
- Usually negative for CK7
Intrahepatic cholangiocarcinoma:
- Glandular pattern with cytoplasmic mucin and desmoplastic stroma
- Negative for hepatocellular markers; positive for CK7
- Albumin ISH is usually positive; however, metastatic adenocarcinoma can also be positive for albumin ISH (usually arising from stomach, lung or pancreas)
Primary liver sarcomas:
- Primary liver sarcomas, such as epithelioid hemangioendothelioma and angiosarcoma, are morphologically indistinguishable from their metastasizing counterparts
- Correlation with clinical and imaging findings is required

Board review style question #1

A 67 year old woman was found to have a large mesenteric mass and multiple liver masses. Both the mesenteric and liver masses are avid on gallium 68 dotatate PET / CT scan. A liver CT guided core needle biopsy was performed and the histologic findings are shown in the image above. The tumor cells are strongly and diffusely positive for CAM 5.2, synaptophysin and chromogranin A. Which of the following statements is true regarding this case?

CD56 immunohistochemical stain is more specific than synaptophysin
CDX2 is usually positive and can be useful to locate the site of origin
Ki67 proliferative index should not be used to grade this tumor
Presence or absence of necrosis is one of the defining features for tumor grading
TTF1 immunohistochemical stain is usually positive

Board review style answer #1

B. CDX2 is usually positive and can be useful to locate the site of origin. CDX2 expression in neuroendocrine tumors (NETs) is usually helpful in pinpointing that the most likely site of origin is the gastrointestinal (GI) tract. Answer C is incorrect because Ki67 proliferative index is part of the grading system for GI neuroendocrine tumors. Answer E is incorrect because TTF1 immunohistochemical stain is usually negative. Answer D is incorrect because the presence or absence of necrosis is not one of the defining features for tumor grading. Tumor grading of well differentiated NETs is based on mitotic rate / proliferative index. Answer A is incorrect because synaptophysin immunohistochemical stain is more specific than CD56.

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Reference: Metastases

Board review style question #2

Which of the following tumors usually show a sinusoidal growth patten when metastasizing to the liver?

Angiosarcoma, lymphoma and breast carcinoma
Colon carcinoma and renal cell carcinoma
Gastrointestinal stromal tumor and solitary fibrous tumor
Leiomyosarcoma and neuroendocrine tumors
Squamous cell carcinoma and acinar cell carcinoma

Board review style answer #2

A. Angiosarcoma, lymphoma and breast carcinoma can show a sinusoidal growth pattern when metastasizing to the liver. Answers B - E are incorrect because these tumors usually show different growth patterns (such as glandular pattern with desmoplastic reaction). Sinusoidal growth patterns are typically not observed in these tumors.

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Reference: Metastases

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